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Sex-specific effects of FRMPD4 in schizophrenia

Possibility of a sex-specific role for a genetic variant in FRMPD4 in schizophrenia, but not cognitive function

Matosin N, Green MJ, Andrews JL, Newell KA, Fernandez-Enright F. Possibility of a sex-specific role for a genetic variant in FRMPD4 in schizophrenia, but not cognitive function. Accepted, NeuroReport. 2015.

Abstract The neurotransmitter disturbances responsible for cognitive dysfunction in schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold proteins. We have recently reported that protein levels of FRMPD4, a multi-scaffolding protein that modulates both Homer1 and post-synaptic density protein 95 (PSD95) activity, is altered in the schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with schizophrenia. We selected and examined a novel single nucleotide polymorphism (SNP), rs5979717 (positioned in the non-coding 3’ untranslated region of FRMPD4 and potentially influencing protein expression) for its association with schizophrenia and nine measures of cognitive function, using age- and sex-matched samples from 268 schizophrenia cases and 268 healthy controls. Brain samples from 20 schizophrenia and 20 healthy control subjects were additionally genotyped, to study the influence of this variant on protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with schizophrenia in female cases (χ2=4.52, p=0.030). No effects of rs5979717 were observed on cognitive performance, or an influence of rs5979717 genotypes on the expression of FRMPD4 proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in schizophrenia, which now warrants further investigation.